Abstract：
Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer with few effective therapeutics. The Notch signaling pathway is evolutionarily conserved with oncogenic properties, but it has not been well studied in uLMS. The purpose of our study was to determine expression of Notch family genes and proteins and to investigate the therapeutic effect of γ-secretase inhibitors (GSIs), indirect inhibitors of Notch signaling, in uLMS. We determined expression of Notch genes and proteins in benign uterine smooth muscle tissue, fibroids, and uLMS samples by immunostaining and in two uLMS cell lines, SK-UT-1B (uterine primary) and SK-LMS-1 (vulvar metastasis) by RT-PCR, Western blot and immunostaining. We exposed our cell lines to GSIs, DAPT and MK-0752, and measured expression of HES1, a downstream effector of Notch. Notch proteins were differentially expressed in uLMS. Expression of NOTCH3 and NOTCH4 was higher in uLMS samples than in benign uterine smooth muscle and fibroids. Expression of NOTCH4 was higher in SK-LMS-1 compared to SK-UT-1B. Exposure of SK-UT-1B and SK-LMS-1 to DAPT and MK-0752 decreased expression of HES1 and decreased uLMS cell viability in a dose- and time-dependent manner that was unique to each GSI. Our findings suggest that GSIs are potential therapeutics for uLMS, albeit with limited efficacy.
摘要：
子宫平滑肌肉瘤（uLMS）是一种罕见的侵袭性癌症，几乎没有有效的治疗方法。Notch信号通路在进化上是保守的，具有致癌特性，但是在uLMS中还没有很好的研究。我们研究的目的是确定Notch家族基因和蛋白质的表达，并研究γ-分泌酶抑制剂（GSI）的治疗效果。Notch信号的间接抑制剂，在uLMS。我们确定了Notch基因和蛋白质在良性子宫平滑肌组织中的表达，肌瘤,和uLMS样品通过免疫染色和在两个uLMS细胞系，SK-UT-1B（子宫原发）和SK-LMS-1（外阴转移）通过RT-PCR，Westernblot和免疫染色。我们将细胞系暴露于GSI,DAPT和MK-0752，并测量了Notch下游效应子HES1的表达。Notch蛋白在uLMS中差异表达。uLMS样本中NOTCH3和NOTCH4的表达高于良性子宫平滑肌和肌瘤。与SK-UT-1B相比，SK-LMS-1中NOTCH4的表达更高。SK-UT-1B和SK-LMS-1暴露于DAPT和MK-0752以剂量和时间依赖性方式降低了HES1的表达并降低了uLMS细胞活力,这对于每个GSI是独特的。我们的研究结果表明，GSI是uLMS的潜在治疗方法，尽管疗效有限。
